The immune system controls the numbers as well as the activation status of the lymphocytes by an active mechanism of homeostatic regulation. Following transfer into lymphopenic conditions, T cells undergo proliferation to compensate lymphocyte deficiency, while T cells remain quiescent after transfer into lymphocyte sufficient hosts. Underlying mechanisms of how such proliferation is induced and regulated are not well understood. We have previously demonstrated heterogeneity of T cell proliferation under lymphopenic conditions: IL-7-dependent slow proliferation and IL-7-independent fast proliferation (referred to as "endogenous proliferation"). Furthermore, endogenous proliferation is found closely associated with differentiation into memory phenotype cells, suggesting that different mechanism appears to be involved in endogenous proliferation. From preliminary studies we found that: 1) initial accumulation of T cells that undergo endogenous proliferation is found mainly in the spleen but not in the mesenteric lymph nodes;2) depletion of gut flora by antibiotic treatment has little effect on endogenous proliferation;3) endogenous proliferation of naive T cells is mainly controlled by the presence of memory T cells;4) repertoire complexity but not total numbers of the memory T cells plays a key role in limiting the endogenous proliferation;5) memory CD4 T cells suppress endogenous proliferation of both naive CD4 and CD8 T cells, while memory CD8 T cells only suppress endogenous proliferation of naive CD8 T cells;6) memory T cells compete with each other, not only to maintain their pool size but also to maximize the repertoire complexity. We hypothesize that endogenous T cell proliferation, triggered by self-antigens expressed on DCs generates a diverse repertoire of memory T cells. These memory cells alter DC functions, further regulating subsequent naive T cell proliferation. Three specific aims are proposed in order to test the hypothesis. Aim #1 will determine if DCs are required for the induction of endogenous proliferation in lymphopenic hosts. Aim #2 will define cellular mechanisms mediating memory T cell inhibition of naive T cell endogenous proliferation. Aim #3 will define the contribution of apoptosis to memory cell homeostasis. The studies are clinically relevant to establish strategies to avoid dysregulated lymphocyte homeostasis, often found in autoimmunity or therapeutic immunoablation. PUBLIC HEALTH RELEVANCE: The immune system evolves an active process of homeostatic control mechanism that ensures its diversity and functionality. Homeostatic dysregulation is believed to link to the development of multiple disorders, including immunodeficiency, autoimmunity and a failure of solid organ transplantation. The current proposal aims to investigate underlying cellular mechanism, and the results will aid our understanding of the immune mechanism and facilitate therapeutic strategies to treat disorders caused by the dysregulation.